The Epstein-Barr virus (EBV) induced gene 2 EBI2, also called GPR183, codifies for a receptor which belongs to the superfamily of Rhodopsin-like 7™ receptors (seven transmembrane segment receptors), also known as G-protein coupled receptors (GPCRs). EBI2, is an orphan G-protein coupled receptor for which no ligand is known. EBI2 was cloned in 1993 as one of the most up-regulated genes (>200 fold) in Epstein-Barr virus (EBV)-infected Burkitt lymphoma cells (Birkenbach, M., et al. (1993). Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J. Virol. 67, 2209-2220.). The EBI2 gene is localized on chromosome 13q32.3. EBI2 shares approximately 35% homology at the amino acid level with the fowlpox virus FPV206, 30-32% with P2Y5 and P2Y9 receptors. EBI2 is also closely related to the orphan 7™ receptor GPR18 and the two lipid receptors cysteinyl leukotriene receptor 1 and −2 (CysLT1, and −2) (25% and 28% homology respectively).
Real-time PCR of EBV-infected cells showed high expression of EBI2 during latent as well as lytic viral replication (Rosenkilde, et al. (2006) Molecular pharmacological phenotyping of EBI2—An orphan seven-transmembrane receptor with constitutive activity. Journal of Biological Chemistry 281 [19], 13199-13208.). Very high expression of the EBI2 gene was reported in peripheral blood mononuclear cells (PBMCs), in lymphoid tissue (spleen and lymph node) and lung tissue (Birkenbach, M., et al. (1993); Rosenkilde, M. M. et al. (2006)). EBI2 expression was shown to be highest in B-lymphocytes, followed by T lymphocytes, NK-cells and lowest in monocytes (Rosenkilde, M. M. et al. (2006), Cahir-McFarland, E. D. et al. (2004). Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells. J. Virol. 78, 4108-4119.). The expression profile of EBI2 suggests a role in immune system modulation. Finally, constitutive signaling through Gαi and cell surface localization of EBI2 was also demonstrated (Rosenkilde, M. M. et al. (2006)).
It is an object of the present invention to identify ligands for EBI2.